Impact of the OncotypeDX score and HER2 RNA PCR levels on HER2-low IHC levels in primary and metastasized tumors

Abstract

Purpose: One-half of hormone receptor-positive (HR +) breast cancer (BC) patients have low expression of HER2 (HER2-low) and may benefit from trastuzumab deruxtecan (TDXd). This study aimed to identify parameters associated with HER2-low levels in primary and metastatic tumors. We specifically sought to determine whether OncotypeDX and HER2 mRNA levels could identify patients who would otherwise be considered HER2-negative by immunohistochemistry (IHC).

Methods: This retrospective analysis of all consecutive HR + patients who underwent OncotypeDX from January 2004 to December 2020 was conducted in a single medical center (n = 1429). We divided HER2-negative cases into HER2-low (IHC = 1 + or 2 + and non-amplified fluorescent situ hybridization) and HER2-0 (IHC = 0). HER2 RT-PCR was evaluated from the OncotypeDX results.

Results: HER2-low cases exhibited significantly higher HER2 RT-PCR scores (p = 2.1e-9), elevated estrogen receptor (ER) levels (p = 0.0114), and larger tumor sizes compared to HER2-0 cases (> 2 cm; 36.6% vs. 22.1%, respectively, p < 0.00001). Primary tumors > 2 cm were more likely to be HER2-low (OR = 2.07, 95% CI: 1.6317 to 2.6475, p < 0.0001). Metastatic BCs expressed higher HER2 IHC scores compared with primary BCs (Wilcoxon signed-rank, p = 0.046). HER2 IHC scores were higher for low-risk vs. medium-risk OncotypeDX (p = 0.0067). No other clinical or pathological parameters were associated with the increase in HER2 levels in the metastatic samples.

Conclusion: It might be beneficial to use clinical data from the primary tumor, including the HER2 RT-PCR score, to determine a HER2-low status.

Keywords: Breast cancer; HER2 low; HER2 negative; Oncotype; RT-PCR.

Fig. 1

Differences between HER2-0 and HER2-low in the OncotypeDX population. a,b HER2 RT-PCR significantly differentiates not only HER2-low from HER2-0 BC (p < 0.0001) but also between HER2 IHC = 0/1 + /2 + categories (p < 0.0001). The black line indicates the group mean. The density indicates the number of overlapping samples. c HER2-low cases in primary tumors expressed higher ER levels (p = 0.0114) and were larger d than HER2-0 cases (p < 0.00001) e Differences between HER2 RT-PCR and HER2 IHC results, stratified by tumor size groups. HER2 RT-PCR significantly differentiates between HER2 IHC scores, especially in > 2 cm tumors, but it does not contribute to the distinction in tumors < 1 cm. Medians are specified under each group

Fig. 2

Metastatic characteristics and differences in HER2 expression between primary and metastatic biopsies. a HER2 IHC scores in primary vs. metastatic BC for each patient in the paired study cohort. Metastatic BCs had a significantly higher HER2 IHC score than primary BCs (one-tailed Wilcoxon signed-rank, p = 0.046). b Differences in HER2 IHC score by OncotypeDX category in primary and metastatic BCs, including all primary BC biopsies and unpaired metastatic BC biopsies. The low-risk OncotypeDX group had a higher IHC score than the medium-risk group (p = 0.0067). Dots represent means. c, d Transition of HER2 expression from primary to metastatic BC. Most of the patients gained or maintained some degree of HER2 expression (65.9%)